Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx- enabled highthroughput medicinal chemistry

• 成果类型: Article
• 署名作者: Kitamura, Seiya; Lin, Ting Hui; Lee, Chang Chun David; Takamura, Akihiro; Kadam, Rameshwar U.; Zhang, Ding; Zhu, Xueyong; Dada, Lucas; Nagai, Emiko; Yu, Wenli; Yao, Yao; Sharpless, K. Barry; Wilson, Ian A.; Wolan, Dennis W.
• 署名单位: Scripps Research Institute; Scripps Research Institute; Scripps Research Institute; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Scripps Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11867
• DOI: 10.1073/pnas.2310677121
• 发表日期: 2024-05-28
• 关键词: o hydrogen-bonds; c-h; vaccine effectiveness; virus hemagglutinin; seasonal influenza; UNITED-STATES; antibody; receptor; ph

摘要

Seasonal and pandemic - associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our smallmolecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur - Fluoride Exchange (SuFEx) click chemistry-based highthroughput medicinal chemistry (HTMC) strategy. A combination of SuFEx - and amide - based lead molecule diversification and structure - guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC 50 cellular antiviral activity against several influenza A group 1 strains. X - ray structures of six of these compounds with HA indicate that the appended moieties occupy additional pockets on the HA surface and increase the binding interaction, where the accumulation of several polar interactions also contributes to the improved affinity. The compounds here represent the most potent HA smallmolecule inhibitors to date. Our divergent HTMC platform is therefore a powerful, rapid, and cost - effective approach to develop bioactive chemical probes and drug - like candidates against viral targets.